Abstract
Adult skeletal muscle regeneration is mainly driven by muscle stem cells (MuSCs), which are highly heterogeneous. Although recent studies have started to characterize the heterogeneity of MuSCs, whether a subset of cells with distinct exists within MuSCs remains unanswered. Here, we find that a population of MuSCs, marked by Gli1 expression, is required for muscle regeneration. The Gli1(+) MuSC population displays advantages in proliferation and differentiation both in vitro and in vivo. Depletion of this population leads to delayed muscle regeneration, while transplanted Gli1(+) MuSCs support muscle regeneration more effectively than Gli1- MuSCs. Further analysis reveals that even in the uninjured muscle, Gli1(+) MuSCs have elevated mTOR signaling activity, increased cell size and mitochondrial numbers compared to Gli1(-) MuSCs, indicating Gli1(+) MuSCs are displaying the features of primed MuSCs. Moreover, Gli1(+) MuSCs greatly contribute to the formation of G(Alert) cells after muscle injury. Collectively, our findings demonstrate that Gli1(+) MuSCs represents a distinct MuSC population which is more active in the homeostatic muscle and enters the cell cycle shortly after injury. This population functions as the tissue-resident sentinel that rapidly responds to injury and initiates muscle regeneration.